The invention relates to a group of novel salts of compounds with the formula and their use in the preparation of pharmaceutical compounds.
Benzazepines with the above formula are known from EP 0733642, EP 0830863, WO00/48601 and WO01/03699. EP 0733642 is related to compounds with the formula (I) and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency. EP 0830863, WO00/48601 and WO01/03699 are related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs, respectively.
Preferred benzazepines are the compounds wherein R1 is a phenylethyl group or a 1-naphtylethyl group, R2 and R3 are both hydrogen and wherein R4 is a biolabile ester group. Suitable groups forming biolabile esters include (C1–C6)-alkyl groups, phenyl or phenyl-(C1–C6)-alkyl groups which are optionally substituted in the phenyl ring by (C1–C6)-alkyl or by a (C2–C6)-alkylene chain bonded to two adjacent carbon atoms, dioxolanylmethyl groups which are optionally substituted in the dioxolane ring by (C1–C6)-alkyl or (C2–C6)-alkanoyloxymethyl groups which are optionally substituted on the oxymethyl group by (C1–C6)-alkyl. Where the group R4 is a by (C1–C6)-alkyl this is preferably an unbranched (C1–C4)-alkyl group. In the most preferred compounds R4 is ethyl.
During further pharmaceutical and clinical development it has appeared that the most preferred compounds have the serious draw-back of being a solid foam. In order to ensure a reproducible constant bioavailability of an active ingredient from a solid pharmaceutical dosage form, it is important that a homogeneous and reproducible modification of the active compound is used. Therefore there always exist certain doubts regarding the reproducibility and constantness of bioavailability in compounds that originate from material that normally is not homogeneous, such as a solid foam.
It is also apparent that it is very difficult to isolate a solid foam on a commercial scale. Further the compound is very sparsely soluble in water and therefore it is very difficult to prepare a formulation of the compound that can be used for IV administration. Up to the present invention an IV formulation only could be prepared from the corresponding diacid (see example II in EP 0733642). This means that for an IV formulation another compound has to be used than for an oral formulation, which is undesirable for a pharmaceutical compound. During further development it appeared that the sodium- and potassium salt of the mono acid are much better soluble in water, but these salts can also only be isolated as a solid foam.